The present invention relates to systems and methods of delivering fluids to a patient of varying concentration and, particularly to the delivery of contrast media used in contrast enhanced imaging procedures in varying concentrations to provide improved concentration or enhancement profiles.
The following information is provided to assist the reader to understand the invention disclosed below and the environment in which it will typically be used. The terms used herein are not intended to be limited to any particular narrow interpretation unless clearly stated otherwise in this document. References set forth herein may facilitate understanding of the present invention or the background of the present invention. The disclosure of all references cited herein are incorporated by reference.
To enhance the contrast of tissue or vessels in radiodiagnostics, particularly in X-Ray Computed Tomography (CT), contrast media are used, which are characterized by the fact that they absorb or scatter X-rays more significantly than does normal tissue. For parenteral administration, there are a multiplicity of tri-iodinated aromatic compounds available, which are characterized by the fact that the introduced hydrophilic residues (side groups) lead to a high tolerance. Even at high concentrations these molecules show almost no chemotoxicity. See, for example, Sovak M. Contrast Media: A journey almost sentimental. Invest Radiol 1994; 29 Supplement1: S4-S14; Speck U. Principles and aims of preclinical testing. Invest Radiol 1994; 29 Supplement 1: S15-S20.
In addition to the use of iodine (I) as an X-ray-absorbing element, gadolinium (Gd) containing MR contrast media have been investigated with respect to X-ray CT in off label-like and/or animal studies. See Gierada D S, Bae K T Gadolinium as a CT Contrast Agent: Assessment in a Porcine Model. Radiology 1999; 210: 829-834.
A distinction is made between ionic and non-ionic contrast media, each of which can be classified further according to monomers or dimers. Generally speaking, ionic contrast media do show adverse reactions more frequently than non-ionic contrast media, which can be partly attributed to the higher osmotic pressure of ionic contrast media as compared to non-ionic contrast media. Ionic contrast media also have a net charge (electronegative) that can lead to side effects, allergic reactions etc. Non-ionic and dimeric iodine containing contrast can be manufactured to be virtually iso-osmolar (that is, having the same osmotic pressure as blood plasma) even at diagnostically relevant concentrations. However, these solutions are highly viscous. In addition the discussion regarding delayed reactions of dimeric X-ray contrast media has not yet been concluded. See for example. S K Morcos, H S Thomsen. Adverse reactions to iodinated contrast media. Eur Radiol 2001; 11: 1267-1275.
A representative list of iodine (I) containing X-ray contrast media and gadolinium (Gd) containing MRI contrast agents are set forth in Table 1. The list is not complete, but sets forth many commonly used contrast media.
TABLE 1Representative X-ray and MRI contrast media.INNIodine containingIonicAcetrizoatemonomersAmidotrizoateDiatrizoateIodamideIoglicic AcidIothalamateIoxitalamis AcidMetrizoateNon-IonicIohexolIomeprolIopamidolIopentolIopromidIoversolIoxilanMetrizamideIodine containingIonicIoxaglatedimersNon-IonicIodixanolIosimenolIotrolanGd containingIonicGadobenatemonomersGadopentetateGadoterateGadoversetamideGadoxetateNon-IonicGadobutrolGadodiamideGadoteridolGd containingIonic—di- and oligomersNon-Ionic—
A number of X-ray-physical parameters of the imaging system or scanner affect the resultant image (for example, X-ray tube: anode material, high voltage, X-ray filter, mAs-product, detector: number of slices and material). X-ray density is an important parameter for the representation of vessels. Typically, high X-ray density is desirable during the period of examination. Not only is the maximum X-ray density important, but a sufficient contrast concentration in the surrounding tissue should be achieved. Further, the concentration should be maintained locally for the X-ray density to attain a desired or optimal (value) beyond the detection period. However, simply increasing the concentration of the contrasting element does not automatically result in an optimal structuring of local and temporal X-ray contrast. In that regard, an increase of the concentration often accompanies a distinct increase in the solutions' viscosity and osmolarity/osmolality. An increased viscosity can limit the rate of administration, and an increased osmolarity/osmolality can limit the tolerability. The correlation between contrast medium concentration and viscosity has been investigated in model studies with respect to the limitation of the application velocity by high contrast media concentrations or viscosities. See F Knollmann, K Schimpf, R Felix. Jodeinbringungsgeschwindigkeit verschieden konzentrierter Röntgen-Kontrastmittel bei schneller venöser Injektion. Fortschr Röntgenstr 2004; 176: 880-884. It has been shown for Iopromide that a higher iodine flux rate of 2400 mg I/s as compared to 2220 mg I/s could be reached for a 300 mg I/ml solution with respect to the higher concentrated 370 mg I/ml solution as a result of an increase of the application flow rate from 6 to 8 ml/s, respectively. These results can be explained on the basis of the Hagen-Poiseuille law for laminar flows, where for constant pressure ΔP the volume flux rate w within vessels of radius r and length l is indirectly proportional to the viscosity η according to w=π/8 r4 ΔP/(1η).
Along with the initial concentration of the stock contrast medium solution, the type of administration plays an important role. A test bolus can be used to correlate administration time with image recording time, to prevent an unnecessary radiation-dose burden, to achieve an appropriate scan timing with respect to a contrast bolus and/or to avoid suboptimal image quality. Further, Bae et al. varied the administration rate in such a manner in attempting to optimize a bolus in the target tissue. Bae K T, Tran H Q, Heiken, J P. Uniform vascular contrast enhancement and reduced contrast medium volume achieved by using exponentially decelerated contrast material injection method. Radiology 2004; 231: 732-736. Using a stock solution with high iodine content and high viscosity, as well as a high osmolarity/osmolality, the rate of administration was selectively reduced. Another administration possibility is to administer additionally a physiologically adjusted saline solution after administering the stock solution, which contains the contrasting element. Aside from the “rinsing effect” of the delivery system and the infusion vein, the advantages of bolus formation and a reduction of contrast medium volume are also being discussed. See Schoellnast H, Tillich M, Deutschmann H A, Deutschmann M J, Fritz G A, Stessel U, Schaffler G J, Uggowitzer M M. Abdominal multidetector row computed tomography: reduction of cost and contrast material dose using saline flush. J Comput Assist Tomogr. 2003; 27: 847-53.
In both cases, profile shaping by deceleration and by use of saline flushes, one is left with the administration of the stock solutions with a high concentration of contrast medium. There is a clear indication that an increased radiographic contrast is always related to the administration of a contrast medium containing, for example, a high iodine concentration, so that strongly increased iodine concentrations will also have to be expected in the infusion vein, up to the vena cava and the right heart. The previous procedure of choice was to increase the radiographic contrast in the target area by always increasing the concentration of the stock solution or by selecting a high rate of administration for this stock solution, resulting automatically in high concentrations all the way up to the right heart along with the concomitant adverse reactions.
It remains desirable to develop improved systems and method for delivering pharmaceuticals such as contrast media to a patient.